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ScienceWeek
NEUROBIOLOGY: ON NEUROTRANSMITTERS
The following points are made by Steven E. Hyman (Current Biology 2005 15:R154):
1) The nervous system processes sensory information and controls behavior by performing an enormous number of computations. These computations occur both within cells and between cells, but it is intercellular information processing, involving complex neural networks, that provides the nervous system with its remarkable functional capacity. The principal cells involved in information processing are neurons, of which there are hundreds, if not thousands of individual cell types based on morphology, location, connectivity and chemistry [1]. In addition to neurons, the other major kind of cell in the nervous system is the glia, which play critical support roles, but which are increasingly seen to function in some aspects of information processing.
2) To provide some idea of the magnitude of the information processing capacity of the human brain, its 10^(11) neurons make, on average, about 1000 connections or synapses, at which communication occurs with other neurons. The range of synapses per cell is very large; the Purkinje cells of the cerebellum may receive 100,000 contacts from input cells. Overall the human brain may contain between 10^(14) and 10^(15) synaptic connections.
3) The diverse chemical substances that carry information between neurons are called "neurotransmitters". Otto Loewi (1873-1961) discovered the first neurotransmitter in 1926 when he demonstrated that acetylcholine carried a chemical signal from the vagus nerve to the heart that slowed the cardiac rhythm. Since that time, more than one hundred substances and a far larger number of receptors have been implicated in synaptic transmission. Because of the remarkably diverse effects of neurotransmitter-mediated signaling at the receptor and post-receptor levels, the number of neurotransmitters, as large as it is, vastly understates the complexity of signaling in the brain.
4) In the nervous systems of higher animals, only a small fraction of neurons are directly involved in transducing sensory information or controlling output cells, such as endocrine, smooth muscle or striated muscle cells. The vast majority form what Nauta [2] called the great intermediate net, which underlies the extraordinary computational power of the brain. The complex set of neuronal networks interposed between input and output neurons form the basis, inter alia, for learning complex motor sequences, for thought, emotion, for "top down" behavioral control and, in humans, for such functions as language, writing poetry and planning wars.
5) In addition to performing present-oriented computations, the nervous system is plastic; it alters itself (forms memories) as it processes information, so that it can respond more adaptively in the future. The subtlety and complexity of the brain's outputs, along with its ability to change in response to new information, is supported by a rich set of mechanisms for cell-cell communication involving, at an anatomical level, intricate but plastic local connections, larger scale neural circuits, and overlying global regulatory systems; and at the chemical level, a large number of neurotransmitters with highly diverse mechanisms for decoding their informational content.[3-5]
References (abridged):
1. Masland, R.H. (2004). Neuronal cell types. Curr. Biol. 14, R497-R500
2. Nauta, W. (1986). Fundamental Neuroanatomy. (New York: Freeman)
3. Nestler, E.J., Hyman, S.E. and Malenka, R.J. (2001). Molecular Neuropharmacology: Foundation for Clinical Neuroscience. (New York: McGraw Hill)
4. Malenka, R.C. (2003). The long-term potential of LTP. Nat. Rev. Neurosci. 4, 923-926
5. Trachtenberg, J.T., Chen, B.E., Knott, G.W., Feng, G., Sanes, J.R., Welker, E. and Svoboda, K. (2002). Long-term in vivo imaging of experience-dependent synaptic plasticity in adult cortex. Nature 420, 788-794
Current Biology http://www.current-biology.com
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NEUROBIOLOGY: ON SYNAPTIC VESICLES
The following points are made by W.J. Tyler and V.N. Murthy (Current Biology 2004 14:R294):
1) Chemical synapses provide the predominant form of fast functional information transfer between neurons in the brain. Synaptic transmission is initiated in a presynaptic neuron when neurotransmitter-containing vesicles release their contents into the synaptic cleft that physically separates the presynaptic and postsynaptic neurons. The released neurotransmitter molecules then bind to their cognate receptors on the postsynaptic neuron, eliciting an array of chemical and electrical changes. Early physiological studies made profound contributions to our understanding of the discrete (quantal) nature of neurotransmitter release and its calcium-dependence. Over the past two decades, our knowledge of synapse operation has been advanced by molecular biological, genetic and biochemical analyses
2) The presynaptic terminal is a compartment where neurotransmitter-containing vesicles cluster near a highly specialized region of the plasma membrane called the "active zone". From there, vesicles release their contents during synaptic transmission. There are exceptions to this general architecture -- for example, presynaptic specializations can occur in dendrites rather than in axons and there are synapses specialized for continuous release that do not have conventional active zones, but have "ribbons". Before neurotransmitter release can occur from a given release site, synaptic vesicles must be sorted, translocated to the active zone, dock and be primed for fusion. Synaptic vesicle recycling is an integral feature of presynaptic function.
3) The presynaptic terminal contains all the necessary molecular machinery that permits it to function as an autonomous, subcellular compartment highly specialized for local vesicle trafficking and recycling. In fact, when axons are severed from their soma, the terminals are capable of remaining functional for quite some time. In addition to synaptic vesicles, the presynaptic terminal is enriched with components required for both exocytosis and endocytosis: these include specialized neurotransmitter transporters to repackage empty vesicles; endosome organelles that might mediate some aspects of vesicle recycling; elements of smooth endoplasmic reticulum that may regulate intracellular Ca2+; mitochondria to meet the energy demands placed on the vesicle cycle; and a matrix of cytoskeletal elements and scaffolding proteins thought to facilitate synaptic vesicle sorting. A large number of cytoplasmic and plasma membrane proteins that appear to play regulatory roles are also found in synapses.
4) Typical presynaptic terminals in the mammalian forebrain contain about 200 synaptic vesicles. Under resting conditions, less than half of these vesicles participate in synaptic transmission. It is unclear why the remaining vesicles do not participate in the synaptic vesicle cycle. A subset of the recycling vesicles -- about 10 typically -- are in apparent contact with the active zone and are called "docked vesicles". Whereas docked vesicles can only be observed through ultrastructural examination, they are thought to be the morphological correlate of a physiologically defined "readily releasable pool". Members of the readily releasable pool are the first vesicles to undergo fusion upon invasion of an action potential into the presynaptic terminal.(1-5)
References:
1. Ceccarelli, B., Hurlbut, W.P., and Mauro, A. (1973). Turnover of transmitter and synaptic vesicles at the frog neuromuscular junction. J. Cell Biol. 57, 499-524
2. Heuser, J.E. and Reese, T.S. (1973). Evidence for recycling of synaptic vesicle membrane during transmitter release at the frog neuromuscular junction. J. Cell Biol. 57, 315-344
3. Murthy, V.N. and De Camilli, P. (2003). Cell biology of the presynaptic terminal. Annu. Rev. Neurosci. 26, 701-728
4. Rettig, J. and Neher, E. (2003). Emerging roles of presynaptic proteins in Ca++-triggered exocytosis. Science 298, 781-785
5. Royle, S.J. and Lagnado, L. (2003). Endocytosis at the synaptic terminal. J. Physiol. 553, 345-355
Current Biology http://www.current-biology.com
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NEUROBIOLOGY: ON SYNAPTIC NEUROTRANSMITTER RELEASE
The following points are made by S.O. Rizzoli and W.J. Betz (Nature 2003 423:591):
1) Synaptic transmission -- the transfer of information between nerve cells -- is the most important aspect of brain function. Roughly speaking, it works as follows. When electrical impulses propagate to the end of a neuron, they evoke the release of chemicals called "neurotransmitters". These diffuse to a nearby neuron and trigger further electrical activity. The neurotransmitters are stored inside the neuron in small, membrane-bounded vesicles(1) -- rather like a soap bubble within a larger soap bubble -- and they are released en masse through a pore that forms when the vesicle membrane fuses with the neuron's surface membrane. It is well established that the vesicle membrane can then collapse into and coalesce with the surface membrane; after that, it can reform and be reused.
2) But the retrieval of membrane components from collapsed vesicles is complex(2), and a different theory, called "kiss-and-run", envisions no vesicular collapse at all; instead, a fusion pore flickers open and then closes. Although the economy of this concept holds considerable intuitive appeal(3), and it is known to occur in secretory processes in other cells(4), solid quantitative evidence of kiss-and-run fusion at conventional synapses has been virtually absent -- until recently. Gandhi and Stevens(5) used different fluorescent markers to track the fate of individual synaptic vesicles, following a single electric shock, in living neurons from the hippocampal region of rat brains. The evidence is that a large fraction of neurotransmitter-release events involve kiss-and-run, not vesicle collapse.
3) Gandhi and Stevens(5) studied these events by using genetic tools to load synaptic vesicles with synaptophluorin, a pH-sensitive fluorescent protein that is attached to a protein in the vesicle membrane. In resting vesicles, the pH is low and the fluorescence of synaptophluorin is quenched. But upon exocytosis -- vesicle fusion with the surface membrane -- the interior of the vesicle becomes open to the solution outside the neuron, allowing protons to escape and so raising the pH. Synaptophluorin then fluoresces brightly, and does so until vesicle retrieval (endocytosis) and reacidification occur.
References (abridged):
1. Katz, B. The Release of Neural Transmitter Substances (Liverpool Univ. Press., 1969)
2. Heuser, J. E. & Reese, T. S. J. Cell Biol. 57, 315-344 (1973)
3. Ceccarelli, B. & Hurlbut, W. P. Physiol. Rev. 60, 396-441 (1980)
4. Alvarez de Toledo, G., Fernandez-Chacon, R. & Fernandez, J. M. Nature 363, 554-558 (1993)
5. Gandhi, S. P. & Stevens, C. F. Nature 423, 607-613 (2003)
Nature http://www.nature.com/nature
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